The genomic loci for the mismatch repair genes hMSH2 and hMSH6 were mapped by fluorescence in situ hybridization, analysis of radiation hybrid panel markers, and linkage analysis of syntenic chromosome regions between human and mouse. Both genes were localized to chromosome 2p21, adjacent to the luteinizing hormone/choriogonadotropin receptor gene (LHCGR; 2p21), telomeric to the D2S123 polymorphic marker, and centromeric to the calmodulin-2 gene (CALM-2; 2p22-21) and son-of-sevenless gene (SOS; 2p22-21). The genomic locations of hMSH2 and hMSH6 appears to be within 1 Mb of each other because they could not be separated by interphase fluorescence in situ hybridization. These results clarify the position of the chromosome 2 hereditary nonpolyposis colorectal cancer locus, which was originally reported to be associated with an adjacent region (chromosome 2p14-16).